o-(chloroacetylcarbamoyl)fumagillol and Pulmonary-Edema

Angiogenesis inhibitors, such as TNP-470 and the nontoxic HPMA copolymer-TNP-470 (caplostatin), are emerging as a class of anticancer drugs. We report that TNP-470 and caplostatin inhibit vascular hyperpermeability of tumor blood vessels as well as that induced in mouse skin by different mediators. Treatment with TNP-470 or angiostatin for 3 days was sufficient to reduce permeability of tumor blood vessels, delayed-type hypersensitivity, and pulmonary edema induced by IL-2. TNP-470 also inhibited VPF/VEGF-induced phosphorylation of VEGFR-2, calcium influx, and RhoA activation in endothelial cells. These results identify an activity of TNP-470, that of inhibiting vessel hyperpermeability. This activity likely contributes to TNP-470's antiangiogenic effect and suggests that caplostatin can be used in the treatment of cancer and inflammation.

Topics: Angiogenesis Inhibitors; Angiostatins; Animals; Calcium; Capillaries; Capillary Permeability; Cell Movement; Cyclohexanes; Endothelial Cells; Female; Hypersensitivity, Delayed; Interleukin-2; Male; Mice; Mice, Inbred C57BL; Mice, SCID; Mitogen-Activated Protein Kinases; Neoplasms; O-(Chloroacetylcarbamoyl)fumagillol; Pulmonary Edema; rhoA GTP-Binding Protein; Sesquiterpenes; Skin; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2